7 research outputs found

    Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

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    Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation

    Functional assays for variants identified through massive parallel sequencing : inputs and outlooks

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    Les avancĂ©es technologiques offrent des opportunitĂ©s sans prĂ©cĂ©dents Ă  la dĂ©tection de variations gĂ©nĂ©tiques. L’interprĂ©tation de l’information gĂ©nĂ©tique grĂące Ă  l’utilisation d’organismes modĂšles fournit des donnĂ©es essentiellesĂ  l’interprĂ©tation de ces variants en gĂ©nĂ©tique mĂ©dicale. Les pathologies neurodĂ©veloppementales, incluant la dĂ©ficience intellectuelle et les troubles du spectre autistique, reprĂ©sentent un dĂ©fi pour l’analyse de variants de sĂ©quence du fait de la forte hĂ©tĂ©rogĂ©nĂ©itĂ© de locus, la contribution Ă©tiologique majeure des variations de novo et les difficultĂ©s d’accĂšs aux types cellulaires d’intĂ©rĂȘt pour les analyses fonctionnelles. Utilisant des phĂ©notypes anatomiques de substitution, nous avons mis en place et validĂ© deux modĂšles poisson zĂšbre de pathologies neurodĂ©veloppementales pour les gĂšnes RORA et SIN3B. La dĂ©termination de la direction d’effet de variants non synonymes grĂące au modĂšle poisson zĂšbre mise en parallĂšle de donnĂ©es radiologiques et cliniques a permis de dĂ©finir deux sous-types nosologiques pour le gĂšne RORA, selon la prĂ©sence ou l’absence de lĂ©sions cĂ©rĂ©belleuses. De plus, nous avons apportĂ© des informations en faveur de la causalitĂ© Ă©tiologique de variants de SIN3B chez des patients atteints de dĂ©ficience intellectuelle associĂ©e Ă  un autisme syndromique en montrant des anomalies de mise en place de la structure cranio-faciale suite Ă  l’inactivation du gĂšne orthologue chez le poisson zĂšbre. Confirmant la haute valeur ajoutĂ©e du poisson zĂšbre pour modĂ©liser les variations gĂ©nĂ©tiques chez des patients atteints de pathologies neurodĂ©veloppementales, ce travail souligne la particuliĂšre informativitĂ© de cette stratĂ©gie en mĂ©decine gĂ©nomique.Technological advances have opened unparalleled opportunities to detect genetic variation. Interpretation of these datausing in vivo disease modeling approaches provides helpful input to inform Medical Genetics clinical practice. Neurodevelopmental disorders, including intellectual disability and autism spectrum disorder, pose a major challengefor genomic data interpretation and disease modeling, given the extensive locus heterogeneity, high contribution of de novo variation to etiologic burden and low accessibility of cell types of interest. Using anatomical surrogate phenotypes in zebrafish, we established relevance to disease and tested pathogenicity of point mutations in novel neurodevelopmental disease causing genes RORA and SIN3B. First, we categorized the RORA-associated disorder in two clinical subtypes depending on the presence of cerebellar features present in addition to intellectual disability and autism spectrum disorder. Nonsynonymous variant testing in zebrafish indicated that there was a diverse direction of variant effect, which was consistent with the clinical subtypes observed. Additionally, we supported SIN3B involvement in a syndromic intellectual disability syndrome by demonstrating that disruption of craniofacial architecture, a comorbid feature, was caused by sin3b targeting in zebrafish. This work highlights the utility of the zebrafish model organism as an informative experimental tool for variant interpretation in genomic medicine, especially in neurodevelopmental disorders

    Objective Evaluation of Clinical Actionability for Genes Involved in Myopathies: 63 Genes with a Medical Value for Patient Care

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    International audienceThe implementation of high-throughput diagnostic sequencing has led to the generation of large amounts of mutational data, making their interpretation more complex and responsible for long delays. It has been important to prioritize certain analyses, particularly those of “actionable” genes in diagnostic situations, involving specific treatment and/or management. In our project, we carried out an objective assessment of the clinical actionability of genes involved in myopathies, for which only few data obtained methodologically exist to date. Using the ClinGen Actionability criteria, we scored the clinical actionability of all 199 genes implicated in myopathies published by FILNEMUS for the “National French consensus on gene Lists for the diagnosis of myopathies using next generation sequencing”. We objectified that 63 myopathy genes were actionable with the currently available data. Among the 36 myopathy genes with the highest actionability scores, only 8 had been scored to date by ClinGen. The data obtained through these methodological tools are an important resource for strategic choices in diagnostic approaches and the management of genetic myopathies. The clinical actionability of genes has to be considered as an evolving concept, in relation to progresses in disease knowledge and therapeutic approaches

    <i>De Novo</i> Mutations in Protein Kinase Genes <i>CAMK2A</i> and <i>CAMK2B</i> Cause Intellectual Disability

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    Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathwa

    De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

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